Drugs for treating respiratory disorders are frequently administered in oral aerosol formulations. One widely used method for dispensing such an aerosol drug formulation involves making a formulation of the drug in a liquified gas known as a propellant. The drug may be dissolved or suspended in the propellant, or in a combination slurry-solution.
The formulation is dispensed by actuation of a dose metering valve affixed to the container the valve being designed to consistently release a fixed, predetermined amount of the drug formulation upon each activation. As the formulation is forced from the container through the dose metering valve by the high vapor pressure of the propellant, the propellant rapidly vaporizes, leaving a fast-moving cloud of very fine particles or droplets of the drug formulation. This cloud is then directed into the mouth of the patient. Concurrently with the activation of the aerosol dose metering valve, the patient inhales the drug formulation particles into the lungs. Systems for dispensing drugs in this way are known as metered dose inhalers (MDIs).
Chlorofluorocarbons (CFCs) have been used extensively as propellants in drug formulations that are delivered to patients via an MDI. However, recent scientific evidence suggests that CFCs damage the Earth's ozone layer. It is believed that ozone blocks harmful ultraviolet rays and that depletion of the ozone layer will result in the incidence of skin cancer. As a result, steps have been taken to reduce CFC production and usage, and recent recommendations have been made that CFC production be virtually discontinued by the end of this century. Until recently, however, few propellant systems have been discovered which are suitable alternatives to the use of CFCs in MDIs.
The nonchlorinated propellants 1,1,1,2-tetrafluoroethane, also known as hydrofluorocarbon (HFC) 134a, and 1,1,1,2,3,3,3-heptafluoropropane, also known as HFC 227, are among the leading candidates for replacement of the ozone-damaging CFC propellants. However, the substitution of a non-CFC propellant for the CFC propellants in MDI formulations is not straightforward. There are drug solubility, drug stability and deliverability problems as well as particle size issues which must be addressed when substituting propellants in an MDI formulation. MDIs contain drugs which are dissolved or suspended as micronized particles, propellants in the form of liquified gases, and surface active compounds, or "surfactants," of a type and in a concentration suitable for suspension or dissolution of the drug. Surfactants are included in the formulation to improve particle dispersibility, prevent deaggregation and improve valve function by virtue of its lubricating properties. In some solution formulations, a co-solvent may be added to enhance drug dissolution, although this practice may have the disadvantage of decreasing the fraction of the metered dose which may be inhaled and contributing to particle size growth.
HFC 134a, or 1,1,1,2-tetrafluoroethane (the names will be used interchangeably herein) is nonflammable, has low toxicity and has vapor pressure suitable for use in aerosols. However, HFC 134a is a very poor solvent which fails to dissolve or adequately disperse commonly used surfactants such as sorbitan trioleate, sorbitan monooleate, lecithins and oleic acid in useful concentrations without the aid of a co-solvent.
Similarly, HFC 227, or 1,1,1,2,3,3,3-heptafluropropane (the names will be used interchangeably herein) is nonflammable, has low toxicity and has a vapor pressure suitable for use in aerosols. However, the polarity and solubility of HFC 227 differ from those of commonly used CFC propellants, and many commonly used surfactants are not soluble or are poorly dispersible in HFC 227.
Flunisolide is an anti-inflammatory synthetic fluorinated corticosteroid having the chemical name 6.alpha.-fluoro-11.beta.,16.alpha.,17,21-tetrahydroxypregna-1,4-diene-3,20 -dionecyclic-16,17-acetal with acetone. Flunisolide is useful for controlling the symptoms of bronchial asthma and in the treatment of seasonal and perennial rhinitis. Presently available flunisolide formulations for MDIs utilize CFCs such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane as propellants. Thus, there remains a need for an environmentally safe flunisolide formulation for MDIs utilizing hydrofluorocarbon propellants such as HFC 134a and HFC 227.
Numerous attempts have been made to formulate aerosols for oral inhalation using non-ozone depleting propellants. However, these formulations generally require the addition of surfactants, polar cosolvents or other adjuvants, and some require the additional manufacturing step of precoating the drug particles with a surfactant prior to dispersal in the propellant.
For example, U.S. Pat. No. 5,225,183 to Purewal et al. discloses MDI formulations which include HFC 134a, a surface active agent, and an adjuvant compound having a higher polarity than HFC 134a. The inclusion of a higher polarity compound in the formulation is said to be critical to the stability and performance of the MDI formulation. The surface active agent is used to stabilize the formulation and lubricate the valve components.
U.S. Pat. No. 5,492,688 to Byron et al. relates to MDI formulations which utilize HFC 134a as the propellant and include a polar surfactant for suspending, solubilizing, wetting and emulsifying the drug constituent and lubricating the valve components of the MDI.
U.S. Pat. No. 5,182,097 to Byron et al. relates to aerosol formulations consisting of 1,1,1,2-tetrafluoroethane, a drug and oleic acid as a surfactant to aid in dispersing the drug in the propellant.
International Application Publication No. W091/04011 relates to medicinal aerosol formulations in which the micronized drug particles are pre-coated with a surfactant prior to dispersal in 1,1,1,2-tetrafluoroethane.
It has now been surprisingly found that HFC 134a and HFC 227 may be used as propellants for medicinal aerosol formulations containing flunisolide without the need for a surfactant and without the need to pre-coat the drug prior to dispersal in the propellant.